Crystal form of tipifarnib and preparation method and pharmaceutical composition thereof

ABSTRACT

The present invention relates to novel crystal forms of tipifarnib. Compared with the prior art, the crystal forms of tipifarnib have advantages in crystallinity, hygroscopicity, morphology, form stability and chemical stability. The present invention also relates to the preparation methods of crystal forms of tipifarnib, pharmaceutical composition thereof and their use in preparation for treating and/or preventing abnormal cell growth diseases.

FIELD OF THE INVENTION

The present invention relates to the technical field of crystallizationin pharmaceutical chemistry. Specifically, the present invention relatesto novel crystals, preparation methods and pharmaceutical compositionsof tipifarnib.

BACKGROUND

Tipifarnib is a farnesyltransferase inhibitor that targets H-RAS orN-RAS mutant cells and has anti-proliferative effects. It is capable ofblocking the farneylation modification of RAS protein, therebyinterfering with RAS localization to the inner surface of the plasmamembrane and subsequent activation of downstream signaling pathways.Tipifarnib shows effective anti-tumor activity.

Tipifarnib has the chemical name of(R)-6-(amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl)-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.The chemical structure is shown in the following formula:

Patent document CN1101392C reported the preparation method of tipifarnibwhich was a racemic mixture and the patent did not disclose anycharacterization data. Patent document CN100567292C reported thepreparation method of tipifarnib, which was a mixture with certainenantiomeric excesses and the patent only mentioned the melting point ofthe mixture. Patent document CN1246318C reported the preparation methodof tipifarnib and the resolution and purification method of tipifarnibin enantiomers. The present inventors have found that tipifarnibprepared by the method described in patent document CN1246318C iscrystalline (herein as “Form A”), but has the defects of lowcrystallinity and poor phase stability. Tipifarnib, reported in patentdocuments CN1101392C and CN100567292C are both mixtures and lackcharacteristic data that accurately describes their physical forms,therefore cannot be considered as sufficiently disclosed content.

In view of the disadvantages in the prior art, it is necessary todevelop new solid forms of tipifarnib with more advantageous propertiesto meet the strict requirements of pharmaceutical preparations on themorphology, stability and other physicochemical properties of activesubstances.

SUMMARY OF THE INVENTION

According to the defects in the prior art, the objective of the presentinvention is to provide new crystalline forms of tipifarnib, preparationmethods, pharmaceutical compositions and uses thereof. The crystallineforms are stable crystalline solids with one or more improvedproperties, especially in the aspects of crystallinity, hygroscopicity,morphology, processability of the formulation and solid-state formstability.

According to the objective of the invention, the first aspect of theinvention is to provide a solid-state tipifarnib Form I (hereinafterreferred to as “Form I”) and its preparation method.

The present invention provides Form I with its structure shown in theformula (I) below:

using Cu-Kα radiation, the X-ray powder diffraction pattern of Form I,expressed as 2θ angles, has the following characteristic peaks:8.4°±0.2°, 11.9°±0.2°, 16.4°±0.2°, 17.0°±0.2°, 18.5°±0.2° and21.7°±0.2°.

In a preferred embodiment of the present invention, the X-ray powderdiffraction pattern of Form I, expressed as 2θ angles, has the followingcharacteristic peaks: 8.4°±0.2°, 11.9°±0.2°, 15.3°±0.2°, 16.4°±0.2°,17.0°±0.2°, 18.0°±0.2°, 18.5°±0.2°, 20.4°±0.2°, 21.3°±0.2°, 21.7°±0.2°,24.8°±0.2° and 26.8°±0.2°.

In a further preferred embodiment of the present invention, the X-raypowder diffraction pattern of Form I, expressed as 2θ angles, has thefollowing characteristic peaks and relative intensities:

Diffraction angel 2θ Relative intensity %  8.4° ± 0.2° 60.2 11.9° ± 0.2°34.6 12.7° ± 0.2° 16.7 14.0° ± 0.2° 9.3 15.3° ± 0.2° 28.4 16.4° ± 0.2°82.7 17.0° ± 0.2° 72.3 17.4° ± 0.2° 32.2 18.0° ± 0.2° 33.8 18.5° ± 0.2°100 19.9° ± 0.2° 13.2 20.4° ± 0.2° 55.2 20.8° ± 0.2° 28.2 21.3° ± 0.2°61.5 21.7° ± 0.2° 61.9 22.9° ± 0.2° 34.1 24.1° ± 0.2° 16.1 24.8° ± 0.2°48.8 25.5° ± 0.2° 11.1 26.8° ± 0.2° 62.5 27.3° ± 0.2° 16.7

Non-restrictively, in one typical embodiment of the present invention,the X-ray powder diffraction pattern of Form I is shown in FIG. 2.

Non-restrictively, the DSC thermogram of Form I is shown in FIG. 3.

Non-restrictively, the TGA thermogram of Form I is shown in FIG. 4.

Non-restrictively, the isothermal sorption plot of Form I is shown inFIG. 5.

Compared with the known Form A, Form I has the following beneficialproperties:

-   -   1) According to the XRPD pattern, Form I has a higher        crystallinity.    -   2) According to the DSC thermogram, Form I has a high melting        point at 235° C.    -   3) According to the isothermal sorption plot, the weight change        of Form I is less than 0.2% between 20 to 80% RH and is not        hygroscopic.    -   4) According to Example 48, Form I still remained its original        form and its purity essentially did not change after having been        placed for 10 days at 60° C. dry condition and 40° C./75% RH        (relative humidity) condition. Form I has better stability.    -   5) According to Comparative Example 1, the crystalline form of        Form I remained unchanged after having been stirred for 3 days        in water while the known Form A transformed to Form I. Form I        has better stability in water.

The above advantageous properties of Form I show that, compared with theknown Form A, Form I has high crystallinity, good stability, lowhygroscopicity, better flowability and processing characteristics(processing such as filtrating, drying, weighing, screening, and so on),which are beneficial to improving the homogeneity of the pharmaceuticalformulations, and may better ensure the pharmaceutically activeingredient itself and the formulations containing tipifarnib, avoid orreduce quality, safety and stability issues during drug manufacturingand/or storage, such as content uniformity and impurity issues, avoidingspecial and expensive package. Moreover, Form I has good stability inwater, is more suitable for the wet granulation process of the soliddosage forms or the preparation of oral suspension dosage form, and canbe kept stable during the manufacture and/or storage of the drug.

According to the objective of the present invention, the presentinvention provides a preparation method of Form I, characterized inthat, the preparation method is selected from any one of the followingmethods, comprising:

-   -   1) Forming a suspension of tipifarnib solids in a solvent,        stirring for crystallization and precipitation, and then        separating crystals and drying to obtain Form I;    -   preferably, the solvent is selected from the group consisting of        ethanol, n-propanol, water, nitromethane, acetone, ethyl        acetate, isopropyl ether, methyl tert-butyl ether,        tetrahydrofuran, acetonitrile, dichloromethane, n-heptane, and        any mixture thereof, more preferably ethyl acetate,        acetonitrile, methyl tert-butyl ether, n-propanol, or any        mixture thereof;    -   preferably, the weight to volume ratio of tipifarnib solids to        the solvent is from 5 mg/1 mL to 100 mg/1 mL, more preferably        from 20 mg/1 mL to 50 mg/1 mL;    -   preferably, the stirring time is from 4 days to 5 days;    -   preferably, the stirring is carried out at 10° C. to 40° C.;    -   preferably, the drying temperature is from 10° C. to 40° C., the        drying time is from 10 hours to 48 hours.    -   2) Forming a solution of tipifarnib solids in a solvent, then        volatilizing to dryness to obtain Form I;    -   preferably, the solvent is selected from the group consisting of        ketones, esters, n-propanol, sec-butanol, butanol, water,        tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane,        toluene and any mixture thereof, more preferably acetone,        dichloromethane, water, acetonitrile or any mixture thereof;    -   preferably, the weight to volume ratio of tipifarnib solids to        the solvent is from 5 mg/1 mL to 50 mg/1 mL, more preferably        from 5 mg/1 mL to 25 mg/1 mL;    -   preferably, the volume ratio of the two solvents in the solvent        mixture is from 1:3 to 3:1;    -   preferably, the volatilizing process is carried out at 25° C. to        40° C.    -   3) Forming a solution of tipifarnib solids in a solvent, cooling        with stirring for crystallization and precipitation, and then        separating crystals and drying to obtain Form I;    -   preferably, the solvent is selected from the group consisting of        alcohols, ketones, esters, acetonitrile and any mixture thereof;        more preferably acetone or isopropanol;    -   preferably, the weight to volume ratio of tipifarnib solids to        the solvent is from 40 mg/1 mL to 150 mg/1 mL, more preferably        from 40 mg/1 mL to 100 mg/l mL;    -   preferably, the temperature of forming solution is from 60° C.        to 75° C., more preferably from 60° C. to 70° C.;    -   preferably, the temperature of crystallization and precipitation        is from −10° C. to 10° C., more preferably from −10° C. to 0°        C.;    -   preferably, the crystallization time is from 1 hour to 10 hours.    -   4) Forming a solution of tipifarnib solids in a co-solvent,        adding anti-solvent, stirring for crystallization and        precipitation, and then separating crystals and drying to obtain        Form I;    -   preferably, the co-solvent is selected from the group consisting        of alcohols, acetone, ethyl acetate, tetrahydrofuran and        nitromethane; more preferably methanol, ethanol, acetone or        tetrahydrofuran;    -   preferably, the weight to volume ratio of tipifarnib solids to        the co-solvent is from 10 mg/1 mL to 50 mg/1 mL, more preferably        from 10 mg/1 mL to 25 mg/1 mL;    -   preferably, the anti-solvent is selected from the group        consisting of water, isopropyl ether, and n-heptane;    -   preferably, the stirring time is from 3 minutes to 60 minutes;    -   preferably, the stirring is carried out at room temperature.    -   5) Forming a suspension of amorphous tipifarnib in a solvent,        stirring for crystallization and precipitation, then separating        crystals and drying to obtain Form I;    -   preferably, the solvent is selected from the group consisting of        alcohols, ketones, esters, ethers, alkanes, tetrahydrofuran and        acetonitrile; more preferably ethyl acetate or acetonitrile;    -   preferably, the weight to volume ratio of amorphous tipifarnib        to the solvent is from 20 mg/1 mL to 100 mg/1 mL, more        preferably from 20 mg/1 mL to 50 mg/1 mL;    -   preferably, the stirring time is from 10 minutes to 20 minutes,        more preferably 10 minutes to 15 minutes.    -   preferably, the stirring is carried out at room temperature.

According to the objective of the invention, the second aspect of theinvention is to provide a solid-state tipifarnib Form II (hereinafterreferred to as “Form II”) and its preparation method.

The present invention provides Form II with its structure shown in theformula (II) below:

Form II is monohydrate, using Cu-Kα radiation, the X-ray powderdiffraction pattern of Form II, expressed as 2θ angles, has thefollowing characteristic peaks: 5.3°±0.2°, 6.8°±0.2°, 8.5°±0.2°,16.3°±0.2°, 18.0°±0.2° and 20.9°±0.2°.

In a preferred embodiment of the present invention, the X-ray powderdiffraction pattern of Form II, expressed as 2θ angles, has thefollowing characteristic peaks: 5.3°±0.2°, 6.8°±0.2°, 8.5°±0.2°,12.8°±0.2°, 13.8°±0.2°, 16.3°±0.2°, 16.9°±0.2°, 17.1°±0.2°, 18.0°±0.2°,18.5°±0.2°, 20.9°±0.2° and 27.9°±0.2°.

In a further preferred embodiment of the present invention, the X-raypowder diffraction pattern of Form II, expressed as 2θ angles, has thefollowing characteristic peaks and relative intensities:

Diffraction angel 2θ Relative intensity %  5.3° ± 0.2° 43.3  6.8° ± 0.2°100  8.5° ± 0.2° 44.4 12.8° ± 0.2° 16.2 13.8° ± 0.2° 12.9 16.3° ± 0.2°45.7 16.9° ± 0.2° 26.5 17.1° ± 0.2° 21.2 18.0° ± 0.2° 78.2 18.5° ± 0.2°21.3 20.4° ± 0.2° 8.4 20.9° ± 0.2° 28.1 21.5° ± 0.2° 6.9 21.9° ± 0.2°9.9 22.3° ± 0.2° 6.6 23.6° ± 0.2° 11.6 24.1° ± 0.2° 9.8 27.1° ± 0.2°11.3 27.9° ± 0.2° 15.7 28.9° ± 0.2° 12.4 30.8° ± 0.2° 10.4.

Non-restrictively, in one typical embodiment of the present invention,the X-ray powder diffraction pattern of Form II is shown in FIG. 6.

Non-restrictively, the DSC thermogram of Form II is shown in FIG. 7.

Non-restrictively, the TGA thermogram of Form II is shown in FIG. 8.

Compared with the known Form A, Form II has the following beneficialproperties:

-   -   1) According to the XPRD pattern, Form II has a higher        crystallinity.    -   2) According to the DSC thermogram, Form II has a high melting        point at 235° C.    -   3) According to Example 48, Form II still remained its original        form and its purity essentially did not change after having been        placed for 10 days at 60° C. dry condition and 40° C./75% RH        condition, respectively. Form II has better stability.    -   4) According to Comparative Example 1, the crystalline form of        Form II remained unchanged after having been stirred for 3 days        in water while the known Form A transformed to Form I. Form II        has better stability in water.

The above advantageous properties of Form II show that, compared withthe known Form A, Form II has high crystallinity, good stability, betterflowability and processing characteristics (processing such asfiltrating, drying, weighing, screening, and so on), which arebeneficial to improving the homogeneity of the pharmaceuticalformulations, and may better ensure the pharmaceutically activeingredient itself and the formulations containing tipifarnib, avoid orreduce quality, safety and stability issues during drug manufacturingand/or storage, such as content uniformity and impurity issues, avoidingspecial and expensive package. Moreover, Form II has good stability inwater, is more suitable for the wet granulation process of the soliddosage form or the preparation of oral suspension dosage form, and canbe kept stable during the manufacture and/or storage of the drug.

According to the objective of the present invention, the presentinvention provides a preparation method of Form II, characterized inthat, the preparation method is selected from any one of the followingmethods, comprising:

-   -   1) Forming a solution of tipifarnib solids in a solvent, then        volatilizing to dryness to obtain Form II;    -   preferably, the solvent is selected from the group consisting of        methanol, ethanol, trifluoroethanol and any mixture thereof,        more preferably methanol;    -   preferably, the weight to volume ratio of tipifarnib solids to        the solvent is from 10 mg/1 mL to 50 mg/1 mL, more preferably        from 10 mg/1 mL to 30 mg/1 mL;    -   preferably, the volatilizing process is carried out at 10° C. to        40° C., more preferably 10° C. to 30° C.    -   2) Forming a suspension of amorphous tipifarnib solids in a        solvent, stirring for crystallization and precipitation, and        then separating crystals and drying to obtain Form II;    -   preferably, the solvent is selected from the group consisting of        an alcohol-water mixture, a ketone-water mixture, a        tetrahydrofuran-water mixture, a 1,4-dioxane-water mixture, an        acetonitrile-water mixture, and a dimethyl sulfoxide-water        mixture, more preferably a dimethyl sulfoxide-water mixture.    -   preferably, the volume percentage of water in the solvent is        from 50% to 100%, more preferably from 85% to 100%;    -   preferably, the weight to volume ratio of tipifarnib solids to        the solvent is from 25 mg/1 mL to 100 mg/1 mL, more preferably        from 25 mg/1 mL to 35 mg/1 mL;    -   preferably, the stirring time is from 10 minutes to 20 minutes,        more preferably from 10 minutes to 15 minutes;    -   preferably, the stirring temperature is from 4° C. to 25° C.;    -   preferably, the drying temperature is from 10° C. to 30° C., the        drying time is from 10 hours to 24 hours.    -   3) Placing amorphous tipifarnib solids in a humidity desiccator        to obtain Form II;    -   preferably, the relative humidity in the humidity desiccator is        from 85% to 100%, more preferably 97%;    -   preferably, the placing time is from 1 day to 7 days, more        preferably 1 day.

According to the objective of the invention, the third aspect of theinvention is to provide a solid-state tipifarnib Form III (hereinafterreferred to as “Form III”) and its preparation method.

The present invention provides Form III with its structure shown in theformula (III) below:

Form III is sesquihydrate, using Cu-Kα radiation, the X-ray powderdiffraction pattern of Form III, expressed as 2θ angles, has thefollowing characteristic peaks: 6.2°±0.2°, 8.8°±0.2°, 15.9°±0.2° and18.2°±0.2°.

In a preferred embodiment of the present invention, the X-ray powderdiffraction pattern of Form III, expressed as 2θ angles, has thefollowing characteristic peaks: 6.2°±0.2°, 8.8°±0.2°, 13.2°±0.2°,15.9°±0.2°, 18.2°±0.2°, 19.8°±0.2°, 22.2°±0.2° and 26.1°±0.2°.

In a further preferred embodiment of the present invention, the X-raypowder diffraction pattern of Form III, expressed as 2θ angles, has thefollowing characteristic peaks and relative intensities:

Diffraction angel 2θ Relative intensity %  6.2° ± 0.2° 10.2  8.8° ± 0.2°100 12.4° ± 0.2° 4.1 13.2° ± 0.2° 7.3 15.9° ± 0.2° 23.9 18.2° ± 0.2°33.2 19.8° ± 0.2° 8.7 21.0° ± 0.2° 3.7 22.2° ± 0.2° 10.8 22.8° ± 0.2°4.4 24.1° ± 0.2° 6.9 26.1° ± 0.2° 9.9 27.6° ± 0.2° 6.6

Non-restrictively, in one typical embodiment of the present invention,the X-ray powder diffraction pattern of Form III is shown in FIG. 9.

Non-restrictively, the DSC thermogram of Form III is shown in FIG. 10.

Non-restrictively, the TGA thermogram of Form III is shown in FIG. 11.

Compared with the known Form A, Form III has the following beneficialproperties:

-   -   1) According to the XRPD pattern, Form III has a higher        crystallinity.    -   2) According to Example 48, Form III remained its original form        and its purity essentially did not change after having been        placed for 10 days at 60° C. dry condition and 40° C./75% RH        condition. Form III has better stability.    -   3) According to Comparative Example 1, the crystalline form of        Form III remained unchanged after having been stirred for 3 days        in water while the known Form A transformed to Form I. Form III        has better stability in water.

The above advantageous properties of Form III show that, compared withthe known Form A, Form III has high crystallinity, good stability, lowhygroscopicity, better flowability and processing characteristics(processing such as filtrating, drying, weighing, screening, and so on),which are beneficial to improving the homogeneity of the pharmaceuticalformulations, and may better ensure the pharmaceutically activeingredient itself and the formulations containing tipifarnib, avoid orreduce quality, safety and stability issues during drug manufacturingand/or storage, such as content uniformity and impurity issues, avoidingspecial and expensive package. Moreover, Form III has good stability inwater, is more suitable for the wet granulation process of the soliddosage form or the preparation of oral suspension dosage form, and canbe kept stable during the manufacture and/or storage of the drug.

According to the objective of the present invention, the presentinvention provides a preparation method of Form III, characterized inthat, the preparation method is selected from any one of the followingmethods, comprising:

-   -   1) Forming a solution of tipifarnib solids in a solvent, cooling        with stirring for crystallization and precipitation, and then        separating crystals and drying to obtain Form III;    -   preferably, the solvent is a water-acetonitrile mixture or a        water-acetone mixture;    -   preferably, the volume percentage of water in the solvent is        from 30% to 50%;    -   preferably, the weight to volume ratio of tipifarnib solids to        the solvent is from 14 mg/1 mL to 25 mg/1 mL;    -   preferably, the temperature of forming solution is from 60° C.        to 70° C.;    -   preferably, the temperature of crystallization and precipitation        is from −10° C. to 0° C.;    -   preferably, the crystallization time is from 1 hour to 24 hours;    -   preferably, the drying temperature is from 10° C. to 40° C., the        drying time is from 10 hours to 24 hours.    -   2) Forming a solution of tipifarnib solids in a co-solvent,        adding an anti-solvent, stirring for crystallization and        precipitation, and then separating crystals and drying to obtain        Form III;    -   preferably, the co-solvent is selected from the group consisting        of acetonitrile, 1,4-dioxane, butanone and isopropyl acetate,        more preferably acetonitrile or 1,4-dioxane;    -   preferably, the weight to volume ratio of tipifarnib solids to        the co-solvent is from 2 mg/1 mL to 25 mg/1 mL, more preferably        10 mg/1 mL to 25 mg/1 mL;    -   preferably, the anti-solvent is water or n-heptane;    -   preferably, the stirring time is from 1 hour to 24 hours;    -   preferably, the stirring is carried out at room temperature;    -   preferably, the drying temperature is from 10° C. to 40° C., the        drying time is from 10 hours to 24 hours.    -   3) Forming a solution of tipifarnib solids in a solvent, then        volatilizing to dryness to obtain Form III;    -   preferably, the solvent is selected from the group consisting of        a nitromethane-water mixture, a butanone-water mixture, an        acetonitrile-water mixture, a tetrahydrofuran-water mixture, and        a 1,4-dioxane-water mixture, more preferably a butanone-water        mixture or a nitromethane-water mixture;    -   preferably, the weight to volume ratio of tipifarnib solids to        the solvent is from 5 mg/1 mL to 10 mg/1 mL;    -   preferably, the volume percentage of water in the solvent is        from 1% to 10%;    -   preferably, the volatilizing temperature is from 10° C. to 30°        C., more preferably from 20° C. to 30° C.

According to the objective of the invention, the fourth aspect of theinvention is to provide a solid-state tipifarnib Form IV (hereinafterreferred to as “Form IV”) and its preparation method.

The present invention provides Form IV with its structure shown in theformula (I) below:

using Cu-Kα radiation, the X-ray powder diffraction pattern of Form IV,expressed as 2θ angles, has the following characteristic peaks:7.5°±0.2°, 13.9°±0.2°, 15.8°±0.2°, 16.5°±0.2°, 17.4°±0.2° and18.1°±0.2°.

In a preferred embodiment of the present invention, the X-ray powderdiffraction pattern of Form IV, expressed as 2θ angles, has thefollowing characteristic peaks: 7.5°±0.2°, 13.9°±0.2°, 15.4°±0.2°,15.8°±0.2°, 16.5°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 20.7°±0.2°, 21.6°±0.2°,24.3°±0.2°, 26.5°±0.2° and 29.1°±0.2°.

In a further preferred embodiment of the present invention, the X-raypowder diffraction pattern of Form IV, expressed as 2θ angles, has thefollowing characteristic peaks and relative intensities:

Diffraction angel 2θ Relative intensity %  7.5° ± 0.2° 51.8 13.9° ± 0.2°22.1 15.4° ± 0.2° 20.4 15.8° ± 0.2° 42.3 16.5° ± 0.2° 100 17.4° ± 0.2°24.7 18.1° ± 0.2° 23 18.9° ± 0.2° 13.4 20.7° ± 0.2° 18.4 21.6° ± 0.2°11.1 23.0° ± 0.2° 16.7 24.3° ± 0.2° 18 24.7° ± 0.2° 13 25.1° ± 0.2° 16.125.9° ± 0.2° 14.5 26.5° ± 0.2° 21.5 27.5° ± 0.2° 19.1 29.1° ± 0.2° 24.1.

Non-restrictively, in one typical embodiment of the present invention,the X-ray powder diffraction pattern of Form IV is shown in FIG. 12.

Non-restrictively, the DSC thermogram of Form IV is shown in FIG. 13.

Non-restrictively, the TGA thermogram of Form IV is shown in FIG. 14.

Compared with the known Form A, Form IV has the following beneficialproperties:

-   -   1) According to the XRPD pattern, Form IV has a higher        crystallinity.    -   2) According to the DSC thermogram, Form IV has a high melting        point at 235° C.    -   3) According to Comparative Example 1, the crystalline form of        Form IV remained unchanged after having been stirred for 3 days        in water while the known Form A transformed to Form I. Form IV        has better stability in water.    -   4) According to Example 48, Form IV still remained its original        form and its purity essentially did not change after having been        placed for 10 days at 60° C./dry condition and 40° C./75% RH        condition. Form IV has better stability.

The above advantageous properties of Form IV show that, compared withthe known Form A, Form IV has high crystallinity, good stability, betterflowability and processing characteristics (processing such asfiltrating, drying, weighing, screening, and so on), which arebeneficial to improving the homogeneity of the pharmaceuticalformulations, and may better ensure the pharmaceutically activeingredient itself and the formulations containing tipifarnib, avoid orreduce quality, safety and stability issues during drug manufacturingand/or storage, such as content uniformity and impurity issues, avoidingspecial and expensive package. Moreover, Form IV has high solubility,and better dissolution and bioavailability.

According to the objective of the present invention, the presentinvention provides a preparation method of Form IV, characterized inthat, the preparation method comprises the following steps:

Forming a solution of tipifarnib solids in a solvent, then volatilizingto dryness to obtain Form IV;

-   -   preferably, the solvent is ethanol or chloroform;    -   preferably, the weight to volume ratio of tipifarnib solids to        the solvent is from 10 mg/1 mL to 25 mg/1 mL;    -   preferably, the volatilizing process is carried out at 40° C. to        50° C.;

According to the objective of the present invention, the fifth aspect ofthe present invention is to provide a solid-state tipifarnib Form V(hereinafter referred to as “Form V”) and its preparation method.

-   -   Using Cu-Kα radiation, the X-ray powder diffraction pattern of        Form V, expressed as 2θ angles, has the following characteristic        peaks: 6.6°±0.2°, 7.8°±0.2°, 8.5°±0.2°, 13.4°±0.2°, 15.1°±0.2°,        15.9°±0.2°, 17.2°±0.2°, 17.7°±0.2°, 17.9°±0.2°, 18.5°±0.2°,        20.2°±0.2° and 20.9°±0.2°.

Non-restrictively, in one typical embodiment of the present invention,the X-ray powder diffraction pattern of Form V is shown in FIG. 15.

The present invention also provides a preparation method of Form V,which comprises the following steps: heating Form II to obtain Form V.

Preferably, the heating rate is from 20° C./minute to 30° C./minute;

Preferably, the end-point temperature of the heating is from 80° C. to120° C.

According to the objective of the present invention, the sixth aspect ofthe present invention is to provide amorphous tipifarnib and itspreparation method.

Non-restrictively, in one typical embodiment of the present invention,the X-ray powder diffraction pattern of amorphous tipifarnib is shown inFIG. 16.

The present invention provides a preparation method of amorphoustipifarnib, which comprises the following steps: forming a solution oftipifarnib solids in a solvent, concentrating the solvent under vacuumto dryness to obtain amorphous tipifarnib.

Preferably, the solvent is dichloromethane;

Preferably, the weight to volume ratio of tipifarnib solids to thesolvent is from 50 mg/1 mL to 100 mg/1 mL;

Preferably, the concentrating under vacuum is carried out at 30° C. to40° C.

In the preparation methods of tipifarnib forms of the present invention,the starting material “tipifarnib” may be a disclosed tipifarnibcompound or the crystalline forms thereof, for example, but not limitedto, tipifarnib prepared according to any one of the preparation methodsin patent documents CN1101392C, CN100567292C and CN1246318C. Thesepatent documents are incorporated herein by reference in their entirety.

The terms used in the present invention include:

The “room temperature” is a temperature between 10° C. to 30° C.

The “overnight” refers to a period of time spanning the night, usually10 hours to 16 hours.

“Stirring” may be carried out by a conventional method in the art, suchas magnetic stirring, mechanical stirring, and the stirring speed is 50r/min to 1800 r/min, preferably 300 r/min to 900 r/min.

“Separation” may be carried out by a conventional method in the art,such as centrifugation or filtration. Preferred method is vacuumfiltration, generally at a pressure less than atmospheric pressure atroom temperature, preferably less than 0.09 MPa.

“Drying” may be performed by conventional methods in the art, such asroom temperature drying, forced air drying or vacuum drying. Dryinginstruments and methods are unrestricted, and may be fume hood, blastoven, spray drying, fluidized bed drying or vacuum oven, and may beperformed under reduced pressure or atmospheric pressure, pressure lessthan 0.09 MPa is preferred. The drying temperature is from 10° C. to 40°C., and the drying time is from 10 hours to 72 hours, preferably from 2hours to 24 hours, more preferably from 2 hours to 8 hours.

The vacuum concentration refers to the operation of a rotary evaporatorto volatilize solvent under pressure less than atmospheric pressure. Theexperimental temperature is from 10° C. to 50° C., and the rotationalspeed is from 50 rpm to 200 rpm.

In the present invention, “crystal” or “crystalline form” refers to thatcharacterized by X-ray powder diffraction pattern, having a uniqueordered molecular arrangement or configuration within the crystallinelattice. It is known to those skilled in the field that the experimentalerror depends on instrumental conditions, sample preparation and samplepurity. The 20 angle of the peaks in the XRPD pattern may change withthe change of instrument and samples. The difference of peak positionmay vary by 1°, 0.8°, 0.5°, 0.3°, 0.1°, etc., depending on theinstruments and samples, and ±0.2° in error is usually allowed.Therefore the difference in peak position should not be regarded as theonly factor. The relative intensity of peaks may change with the changeof sample, sample preparation, and other experimental conditions.Therefore, the order of peak intensities should not be regarded as theonly or the determining factor. Due to the effect of experimentalfactors including sample height, peak position may shift. Generally, asmall amount of peak shifting is acceptable. Hence, it is easilyunderstood for those skilled in the field that any crystalline formhaving the same or similar x-ray powder diffraction pattern as that ofthe crystalline form in the present invention should be within the scopeof the present invention. “Single crystalline form” refers to acrystalline form confirmed by x-ray powder diffraction as a single form.

Tipifarnib froms of the present invention are substantially pure,single, and substantially free of any other crystalline or amorphousforms. As used herein, “substantially pure” when used in reference to anew crystalline form means that the new crystalline form comprises atleast 80% by weight of the present compound, more preferably at least90% (by weight), especially at least 95% (by weight), especially atleast 99% (by weight).

The seventh aspect of the invention is to provide a pharmaceuticalcomposition, which comprises a therapeutically and/or preventivelyeffective amount of pharmaceutical active ingredient selected from thecrystalline forms of tipifarnib of the present invention or thecrystalline forms of tipifarnib prepared by the preparation methods ofthe present invention, and at least one pharmaceutically acceptableexcipient. Wherein tipifarnib forms of the present invention includeForm I, Form II, Form III and Form IV. In addition, the pharmaceuticalcomposition may also comprise other pharmaceutically acceptablecrystalline forms (e.g. Form V) or amorphous forms of tipifarnib.

The excipients of pharmaceutical composition are known to those skilledin the field, and the selection of the type, usage and amount of theexcipients is also known to those skilled in the field. For example,they include carbohydrate, cellulose and its derivative, starch ormodified starch, adhesives such as microcrystalline cellulose, ethylcellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose,hydroxyethyl cellulose, disintegrants such as sodium glycolate starch,crospovidone, croscarmellose, sodium carboxymethylcellulose, cornstarch,lubricant such as stearic acid, magnesium stearate, sodium stearylfumarate, polyethyleneglycol, filler such as kaolin.

The administration route of pharmaceutical composition includes oraladministration, intravenous subcutaneous injection, tissue injection,transdermal administration, rectal administration, etc. Thepharmaceutical composition may be prepared as a certain dosage formdepending on the route of administration or need, and may be solid orliquid. Solid oral dosage forms, including, for example, tablets,powders, pills and capsules; liquid oral dosage forms, including, forexample, solutions, syrups, suspensions and elixirs, injectablepreparations, including, for example, solutions and suspensions, sprayor epithelial administration.

The formulation may be suitable for immediate, sustained or controlledrelease of the active ingredient of the drug. It may be a conventional,dispersible, chewable, buccal soluble or rapidly dissolvableformulation.

The pharmaceutical composition may be prepared by the method commonlyknown to those skilled in the art. In preparation of the pharmaceuticalcomposition, the tipifarnib forms of the present invention (include FormI, Form II, Form II and Form IV) are mixed with one or morepharmaceutically acceptable excipients, optionally with otherpharmaceutically acceptable polymorphs and amorphous form of tipifarnib,optionally with one or more other active ingredients. Solid formulationsmay be prepared by direct mixing, granulation and other processes.

According to the objective of the present invention, the presentinvention provides the crystalline forms of tipifarnib or thecrystalline forms of tipifarnib prepared by the preparation methods ofthe present invention in the preparation of a medicament for thetreatment and/or prevention of abnormal cell growth diseases; thediseases include but not limited to solid tumors and blood cancersassociated with RAS mutation or over expression, such as lung cancer,pancreatic cancer, colon cancer, thyroid follicular cancer,myelodysplastic syndrome, interstitial cell tumor, melanoma, teratoma,neuroblastoma, glioma, epidermal cancer such as head and neck squamouscell carcinoma, salivary gland cancer, skin benign tumor, breast cancer,kidney cancer, bone cancer, ovarian cancer, bladder cancer, livercancer, multiple neurofibromatosis, hematologic lymphoma such asperipheral T lymphoma, myeloid leukemia, myelodysplastic syndrome (MDS),chronic granulocytic leukemia, and so on. According to an objective ofthe present invention, the present invention provides a method oftreating and/or preventing of abnormal cell growth diseases, the methodcomprising administering to a patient in need thereof a therapeuticallyand/or prophylactically effective amount of the foregoing pharmaceuticalcompositions of Form I, Form II, Form III and Form IV. The diseases arethe same as those mentioned above in this specification.

Active compounds are usually effective in large doses. In general it iscontemplated that an effective amount would be from 0.0001 mg/kg to 100mg/kg body weight, and in particular from 0.001 mg/kg to 10 mg/kg bodyweight. It may be appropriate to administe the required dose as two,three, four or more sub-doses at appropriate intervals throughout theday. Said sub-doses may be formulated as unit dosage forms, for example,containing 0.01 to 500 mg, and in particular 0.1 mg to 200 mg of activeingredient per unit dosage from.

DESCRIPTION OF DRAWINGS

FIG. 1 is the XPRD pattern of tipifarnib prepared according to patentdocument CN1246318C.

FIG. 2 is the XPRD pattern of tipifarnib Form I of the presentinvention.

FIG. 3 is the DSC thermogram of tipifarnib Form I of the presentinvention.

FIG. 4 is the TGA thermogram of tipifarnib Form I of the presentinvention.

FIG. 5 is the isothermal sorption plot of tipifarnib Form I of thepresent invention.

FIG. 6 is the XPRD pattern of tipifarnib Form II of the presentinvention.

FIG. 7 is the DSC thermogram of tipifarnib Form II of the presentinvention.

FIG. 8 is the TGA thermogram of tipifarnib Form II of the presentinvention.

FIG. 9 is the XPRD pattern of tipifarnib Form III of the presentinvention.

FIG. 10 is the DSC thermogram of tipifarnib Form III of the presentinvention.

FIG. 11 is the TGA thermogram of tipifarnib Form III of the presentinvention.

FIG. 12 is the XPRD pattern of tipifarnib Form IV of the presentinvention.

FIG. 13 is the DSC thermogram of tipifarnib Form IV of the presentinvention.

FIG. 14 is the TGA thermogram of tipifarnib Form IV of the presentinvention.

FIG. 15 is the XPRD pattern of tipifarnib Form V of the presentinvention.

FIG. 16 is the XPRD pattern of amorphous tipifarnib of the presentinvention.

SPECIFIC IMPLEMENTATIONS

The following examples help to further understand the present invention,but are not intended to limit the contents of the present invention.

Instruments and characterization methods:

-   -   X-ray powder diffraction (XRPD): performed on Bruder D8 Advance        diffractometer. The samples were tested at room temperature        under the following conditions: scan range 3-40° 2θ, step size        0.02° 2θ, and speed 0.2 s/step.

Differential thermal analysis data were collected on TA Instruments Q200MDSC. Method: place 1 mg to 10 mg sample into an sealed aluminum pan,ramp to 250° C. at a rate of 10° C./min under the protection of dry N₂purge at 40 mL/min.

Thermogravimetric analysis data were collected on TA Instruments Q500TGA. Method: place 5 mg to 15 mg sample into a platinum pan, use highresolution method, ramp to 350° C. at a rate of 10° C./min under theprotection of dry N₂ purge at 40 mL/min.

Infrared spectrometry (IR) data were collected using Burker Tensor 27FT-IR. The instrument control software and data analysis software areOPUS. Usually, ATR equipment is used to collect infrared absorptionspectra in the range of 600 cm⁻¹-4000 cm⁻¹, the scanning time for sampleand blank background is 16 seconds, and the instrument resolution is 4cm⁻¹.

Dynamic vapor sorption data and isothermal sorption data were collectedon TA Instruments Q5000 TGA. Method: place 1 mg to 10 mg sample into aplatinum pan; the weight change of the sample during the change inrelative humidity from 0% to 80% to 0% was measured.

¹H Nuclear magnetic resonance spectrum (¹H-NMR) data were collected onBruker Avance II DMX 400 MHz nuclear magnetic resonance spectrometer.Method: place 1 mg to 5 mg sample and dissolve it into a nuclearmagnetic sample tube with 0.5 mL deuterated reagent for detection.

Unless particularly specified, all Examples were conducted at roomtemperature, solvent ratio is volume ratio.

Unless particularly specified, all reagents used in the Examples werecommercially available.

Preparation Example 1

Tipifarnib was prepared by referencing the methods described in thepreparation, resolution and purification steps of the compound (I) inthe specification of patent document CN1246318C.

The XRPD pattern is shown in FIG. 1.

The above characterization results indicate that tipifarnib obtained bythe method described in the preparation of compound (I) of patentdocument CN1246318C is Form A with low crystallinity.

Example 1

Took 200 mg tipifarnib of Preparation Example 1, added 2.0 mLdichloromethane to obtain a clear solution, concentrated the solutionunder vacuum at 40° C. to obtain amorphous tipifarnib; 90% yield.

The XRPD pattern is shown in FIG. 16.

Example 2

Took 20 mg tipifarnib of Preparation Example 1, added 1.0 mL ethylacetate to obtain a suspension, stirred at 10° C. for crystallizationand precipitation for 4 days, vacuum filtrated, and then vacuum dried at40° C. for 10 hours to obtain 18 mg tipifarnib Form I; 90% yield.

Its XRPD pattern is shown in FIG. 2.

Its DSC thermogram is shown in FIG. 3.

Its TGA thermogram is shown in FIG. 4.

Its isothermal sorption plot is shown in FIG. 5.

Example 3

Took 100 mg tipifarnib of Preparation Example 1, added 0.4 mLacetonitrile and 1.6 mL methyl tert-butyl ether to obtain a suspension,stirred at 40° C. for crystallization and precipitation for 5 days,vacuum filtrated, and then vacuum dried at 60° C. for 48 hours to obtain88 mg tipifarnib Form I; 88% yield.

Example 4

Took 30 mg tipifarnib of Preparation Example 1, added 0.3 mL n-propanolto obtain a suspension, stirred at 25° C. for crystallization andprecipitation for 4 days, vacuum filtrated, and then vacuum dried at 40°C. for 24 hours to obtain 25 mg tipifarnib Form I; 83.3% yield.

Example 5

Took 40 mg tipifarnib of Preparation Example 1, added 0.5 mL ethanol toobtain a suspension, stirred at 30° C. for crystallization andprecipitation for 4 days, vacuum filtrated, and then vacuum dried at 50°C. for 30 hours to obtain 28 mg tipifarnib Form I; 70% yield.

Example 6

Form I can also be obtained by replaing the solvent in Example 5 withthe following table.

Experiment Number Solvent 1 Solvent 2 Experiment 1 Ethanol NitromethaneExperiment 2 Ethanol Ethyl acetate Experiment 3 Ethanol n-HeptaneExperiment 4 Water Acetone Experiment 5 Water Tetrahydrofuran Experiment6 Dichloromethane Ethyl acetate Experiment 7 n-Heptane Isopropyl ether

Example 7

Took 10 mg tipifarnib of Preparation Example 1, added 2.0 mL acetone toobtain a clear solution, volatilized at 25° C. to dryness to obtain 9.5mg tipifarnib Form I; 95% yield.

Example 8

Took 10 mg tipifarnib of Preparation Example 1, added 0.4 mLdichloromethane to obtain a clear solution, volatilized at 40° C. todryness to obtain 9.6 mg tipifarnib Form 1; 96% yield.

Example 9

Took 10 mg tipifarnib of Preparation Example 1, added 1.0 mLacetonitrile/water (3:1) to obtain a clear solution, volatilized at 40°C. to dryness to obtain 8.9 mg tipifarnib Form I; 89% yield.

Example 10

Took 50 mg tipifarnib of Preparation Example 1, added 1.0 mLmethanol/acetone (3:1) to obtain a clear solution, volatilized at 30° C.to dryness to obtain 40 mg tipifarnib Form 1; 80% yield.

Example 11

Form I can also be obtained by replacing the solvents in Example 10 withthe following table.

Experiment Number Solvent 1 Solvent 2 Experiment 1 Methanol WaterExperiment 2 Methanol Butanone Experiment 3 Ethanol Ethyl acetateExperiment 4 Isopropanol Isopropyl acetate Experiment 5 sec-Butanol —Experiment 6 Tetrahydrofuran Water Experiment 7 1,4-dioxane — Experiment8 Acetonitrile Toluene

Example 12

Took 200 mg tipifarnib of Preparation Example 1, added 0.5 mL acetone at60° C. to obtain a solution, stirred at −10° C. for 10 hours forcrystallization and precipitation, vacuum filtrated, and then vacuumdried at room temperature overnight to obtain 17.5 mg tipifarnib Form I;88% yield.

Example 13

Took 30 mg tipifarnib of Preparation Example 1, added 0.3 mL isopropanolat 70° C. to obtain a solution, stirred at 0° C. for 1 hour forcrystallization and precipitation, vacuum filtrated, and then vacuumdried at room temperature overnight to obtain 26 mg tipifarnib Form I;87% yield.

Example 14

Took 150 mg tipifarnib of Preparation Example 1, added 1.0 mL methanolat 75° C. to obtain a solution, stirred at 10° C. for 2 hours forcrystallization and precipitation, vacuum filtrated, and then vacuumdried at room temperature overnight to obtain 110 mg tipifarnib Form I;73% yield.

Example 15

Form I can also be obtained by replacing the solvent in Example 14 withthe following table.

Experiment Number Solvent 1 Solvent 2 Experiment 1 Methanol ButanoneExperiment 2 Ethanol Ethyl acetate Experiment 3 n-Propanol Isopropylacetate Experiment 4 sec-butanol — Experiment 5 n-Butanol — Experiment 6Acetonitrile — Experiment 7 Acetonitrile Ethyl acetate Experiment 8Acetonitrile Acetone

Example 16

Placed 10 mg tipifarnib of Preparation Example 1 in 0.4 mL methanol toobtain a solution, added 5.2 mL isopropyl ether, stirred at roomtemperature for 3 minutes for crystallization and precipitation, vacuumfiltrated, and then vacuum dried at room temperature for 48 hours toobtain 8.4 mg tipifarnib Form I; 84% yield.

Example 17

Placed 10 mg tipifarnib of Preparation Example 1 in 0.4 mLtetrahydrofuran to obtain a solution, added 4.0 mL n-heptane, stirredfor 60 minutes for crystallization and precipitation, vacuum filtrated,and then vacuum dried at room temperature for 24 hours to obtain 7.8 mgtipifarnib Form I; 78% yield.

Example 18

Placed 10 mg tipifarnib of Preparation Example 1 in 1.0 mL acetone toobtain a solution, added 5.0 mL isopropyl ether, stirred for 30 minutesfor crystallization and precipitation, vacuum filtrated, and then vacuumdried at room temperature for 10 hours to obtain 7.6 mg tipifarnib FormI; 76% yield.

Example 19

Placed 10 mg tipifarnib of Preparation Example 1 in 0.2 mL ethanol toobtain a solution, added 1.8 mL water, stirred for 30 minutes forcrystallization and precipitation, vacuum filtrated, and then vacuumdried at room temperature for 10 hours to obtain 6.5 mg tipifarnib FormI; 65% yield.

Example 20

Placed 40 mg tipifarnib of Preparation Example 1 in 1.0 mLtrifluoroethanol to obtain a solution, added 1.8 mL water, stirred for30 minutes for crystallization and precipitation, vacuum filtrated, andthen vacuum dried at room temperature for 10 hours to obtain 26 mgtipifarnib Form I; 65% yield.

Example 21

Form I can also be obtained by replacing the solvent in Example 20 withthe following table.

Experiment Number Co-solvent Anti-solvent Experiment 1 TrifluoroethanolIsopropyl ether Experiment 2 Isopropanol n-Heptane Experiment 3n-Propanol Water Experiment 4 Ethyl acetate n-Heptane Experiment 5Nitromethane Isopropyl ether

Example 22

Took 15 mg tipifarnib of Preparation Example 1, added 0.3 mL ethylacetate to obtain a suspension, stirred at room temperature for 15minutes for crystallization and precipitation, vacuum filtrated, andthen vacuum dried at room temperature for 48 hours to obtain 12 mgtipifarnib Form I; 80% yield.

Example 23

Took 15 mg amorphous tipifarnib of Example 1, added 0.75 mL acetonitrileto obtain a suspension, stirred at room temperature for 15 minutes forcrystallization and precipitation, vacuum filtrated, and then vacuumdried at room temperature for 24 hours to obtain 12.3 mg tipifarnib FormI; 82% yield.

Example 24

Took 15 mg amorphous tipifarnib of Example 1, added 0.15 mL ethanol toobtain a suspension, stirred at room temperature for 20 minutes forcrystallization and precipitation, vacuum filtrated, and then vacuumdried at room temperature for 24 hours to obtain 10.5 mg tipifarnib FormI; 70% yield.

Example 25

Form I can also be obtained by replacing the solvent in Example 24 withthe following table.

Experiment Number Solvent Experiment 1 Methanol Experiment 2 IsopropanolExperiment 3 Acetone Experiment 4 Butanone Experiment 5 Ethyl acetateExperiment 6 Isopropyl acetate Experiment 7 Isopropyl ether Experiment 8methyl tert-butyl ether Experiment 9 n-Heptane Experiment 10Methylcyclohexane Experiment 11 Tetrahydrofuran

XRPD patterns, DSC thermograms, TGA thermograms (not shown) of thesamples prepared in Examples 3 to 25 are the same as or similar to thatof the sample prepared in Example 2, indicating the crystalline formsobtained in Examples 3 to 25 are the same as that of Example 2.

Example 26

Took 12 mg tipifarnib of Preparation Example 1, added 0.4 mL methanol toobtain a clear solution, volatilized at 10° C. to dryness to obtain 10mg tipifarnib Form II; 80% yield.

Its XRPD pattern is shown in FIG. 6.

Its DSC thermogram is shown in FIG. 7.

Its TGA thermogram is shown in FIG. 8.

Example 27

Took 10 mg tipifarnib of Preparation Example 1, added 1.0 mL methanol toobtain a clear solution, volatilized at 30° C. to dryness to obtain 24mg tipifarnib Form II; 77% yield.

Example 28

Took 50 mg tipifarnib of Preparation Example 1, added 1.0 mLtrifluoroethanol to obtain a clear solution, volatilized at 40° C. todryness to obtain 38 mg tipifarnib Form II; 73% yield.

Example 29

Form II can also be obtained by replacing the solvent in Example 28 withthe following table.

Experiment Number Solvent 1 Solvent 2 Experiment 1 Ethanol — Experiment2 Ethanol Methanol Experiment 3 Ethanol Trifluoroethanol Experiment 4Methanol Trifluoroethanol

Example 30

Took 15 mg amorphous tipifarnib of Example 1, added 0.6 mL water toobtain a suspension, stirred at 25° C. for 15 minutes forcrystallization and precipitation, vacuum filtrated, and then vacuumdried at 10° C. for 24 hours to obtain 14.1 mg tipifarnib Form II; 91%yield.

Example 31

Took 15.75 mg amorphous tipifarnib of Example 1, added a water-dimethylsulfoxide solution (containing 85% water) 0.45 mL to obtain asuspension, stirred at 4° C. for 10 minutes for crystallization andprecipitation, vacuum filtrated, and then vacuum dried at 30° C. for 10hours to obtain 13.5 mg tipifarnib Form II; 83% yield.

Example 32

Took 10 mg amorphous tipifarnib of Example 1, added a water-ethanolsolution (containing 50% water) 0.1 mL to obtain a suspension, stirredat 10° C. for 20 minutes for crystallization and precipitation, vacuumfiltrated, and then vacuum dried at 25° C. for 20 hours to obtain 8.0 mgtipifarnib Form II; 77% yield.

Example 33

Form II can also be obtained by replacing the solvent in Example 32 withthe following table.

Experiment Number Solvent 1 Solvent 2 Experiment 1 Water MethanolExperiment 2 Water Isopropanol Experiment 3 Water n-Propanol Experiment4 Water Acetone Experiment 5 Water Tetrahydrofuran Experiment 6 Water1,4-dioxane Experiment 7 Water Acetonitrile

Example 34

Took 15 mg amorphous tipifarnib of Example 1, placed in a humiditydessicator with relative humidity of 97% for 1 day to obtain 14 mgtipifarnib Form II; 90% yield.

XRPD patterns, DSC thermograms, TGA thermograms (not shown) of thesamples prepared in Examples 27 to 34 are the same as or similar to thatof the sample prepared in Example 26, indicating the crystalline formsobtained in Examples 27 to 34 are the same as that of Example 26.

Example 35

Took 50 mg tipifarnib of Preparation Example 1, added a water-acetonesolution (containing 50% water) 2.0 mL at 60° C. to obtain a clearsolution, stirred at −10° C. for 1 hour for crystallization andprecipitation, vacuum filtrated, and then vacuum dried at roomtemperature for 10 hours to obtain 43 mg tipifarnib Form III; 82% yield.

Its XRPD pattern is shown in FIG. 9.

Its DSC thermogram is shown in FIG. 10.

Its TGA thermogram is shown in FIG. 11.

Example 36

Took 49 mg tipifarnib of Preparation Example 1, added awater-acetonitrile solution (containing 30% water) 3.5 mL at 70° C. toobtain a clear solution, stirred at 0° C. for 24 hours forcrystallization and precipitation, vacuum filtrated, and then vacuumdried at room temperature for 24 hours to obtain 45 mg tipifarnib FormIII; 87% yield.

Example 37

Placed 10 mg tipifarnib of Preparation Example 1 in 1.0 mL acetonitrileto obtain a solution, added 15.0 mL water, stirred at room temperaturefor 24 hours for crystallization and precipitation, vacuum filtrated,and then vacuum dried at 10° C. for 24 hours to obtain 8.0 mg tipifarnibForm III; 76% yield.

Example 38

Placed 10 mg tipifarnib of Preparation Example 1 in 0.4 mL 1,4-dioxaneto obtain a clear solution, added 10.0 mL n-heptane, stirred at roomtemperature for 1 hour for crystallization and precipitation, vacuumfiltrated, and then vacuum dried at 40° C. for 10 hours to obtain 8.5 mgtipifarnib Form III; 81% yield.

Example 39

Placed 10 mg tipifarnib of Preparation Example 1 in 5.0 mL isopropylacetate to obtain a clear solution, added 15.0 mL n-heptane drop-wisely,stirred at room temperature for 2 hours for crystallization andprecipitation, vacuum filtrated, and then vacuum dried at 30° C. for 12hours to obtain 7.3 mg tipifarnib Form III; 69% yield.

Example 40

Form III can also be obtained by replacing the solvent in Example 39with the following table.

Experiment Number Co-solvent Anti-solvent Experiment 1 1,4-dioxane WaterExperiment 2 Butanone n-Heptane

Example 41

Took 5 mg tipifarnib of Preparation Example 1, added a water-butanonesolution (containing 1% water) 1.0 mL to obtain a clear solution,volatilized at 30° C. to dryness to obtain 4 mg tipifarnib Form III; 76%yield.

Example 42

Took 10 mg tipifarnib of Preparation Example 1, added awater-nitromethane solution (containing 2% water) 2.0 mL to obtain aclear solution, volatilized at 20° C. to dryness to obtain 7.6 mgtipifarnib Form III; 72% yield.

Example 43

Took 8 mg tipifarnib of Preparation Example 1, added awater-acetonitrile solution (containing 10% water) 1.0 mL to obtain aclear solution, volatilized at 10° C. to dryness to obtain 5.6 mgtipifarnib Form III; 66% yield.

Example 44

Form III can also be obtained by replacing the solvent in Example 43with the following table.

Experiment Number Solvent 1 Solvent 2 Experiment 1 Tetrahydrofuran WaterExperiment 2 1,4-Dioxane Water

XRPD patterns, DSC thermograms, TGA thermograms (not shown) of thesamples prepared in Examples 36 to 44 are the same as or similar to thatof the sample prepared in Example 35, indicating the crystalline formsobtained in Examples 36 to 44 are the same as that of Example 35.

Example 45

Took 10 mg tipifarnib of Preparation Example 1, added 1.0 mL ethanol toobtain a clear solution, volatilized at 40° C. to dryness to obtain 9.0mg tipifarnib Form IV; 90% yield.

Its XRPD pattern is shown in FIG. 12.

Its DSC thermogram is shown in FIG. 13.

Its TGA thermogram is shown in FIG. 14.

Example 46

Took 10 mg tipifarnib of Preparation Example 1, added 0.4 mL chloroformto obtain a clear solution, volatilized at 50° C. to dryness to obtain8.5 mg tipifarnib Form IV; 85% yield.

Example 47

Took 10 mg tipifarnib Form II of Example 26, heated to 120° C. at therate of 30° C./min to obtain tipifarnib Form V.

Its XRPD pattern is shown in FIG. 15.

Example 48

Phase and chemical stability experiments: took 20 mg tipifarnib Form I,20 mg Form II, 20 mg Form III and 20 mg Form IV of the presentinvention, placed at 60° C. dry condition and 40° C./75% RH conditionrespectively, and then analyzed by XRD at the corresponding time.

10 days test results Form Condition Form Purity (%) Form I 60° C./dryingTipifarnib Form I 99.72 40° C./75% RH Tipifarnib Form I 99.61 60°C./drying Tipifarnib Form II 99.84 Form II 40° C./75% RH Tipifarnib FormII 99.86 60° C./drying Tipifarnib Form III 99.80 Form III 40° C./75% RHTipifarnib Form III 99.80 60° C./drying Tipifarnib Form IV 99.85 Form IV40° C./75% RH Tipifarnib Form IV 99.73

Tipifarnib Form I, Form II, Form III and Form IV of the presentinvention still remained their original forms and their purityessentially did not decrease after having been placed for 10 days at 60°C. drying condition and 40° C./75% RH condition, respectively. Theseresults show that tipifarnib Form I, Form II, Form III and Form IVprepared by the present invention have good phase and chemicalstability.

Example 49 Preparation of Tablet Core:

Mixed well 100 g tipifarnib Form I or Form II or Form III or Form IV(active ingredient basis) of the present invention, 570 g lactose and200 g starch and then wetted with a solution of 5 g sodium dodecylsulfate and 10 g polyvinylpyrrolidone in about 200 mL water. The wettedpowder mixture was sifted, dried and then sifted again, then 100 gmicrocrystalline cellulose and 15 g hydrogenated vegetable oil wereadded. Mixed well the whole thing and compressed into tablets, resulting10000 tablets, each comprising 10 mg active ingredient.

Coating:

To a solution of 10 g methylcellulose in 75 ml denatured ethanol added asolution of 5 g ethylcellulose in 150 ml dichloromethane, followed byaddition of 75 ml dichloromethane and 2.5 ml 1,2,3-propanetriol. Melted10 g polyethylene glycol and dissolved it in 75 ml dichloromethane. Thelatter solution was added to the former solution and then added 2.5 gmagnesium octadecanoate, 5 g polyvinylpyrrolidone and 30 ml concentratedcolour suspension and the whole thing was homogenated. The resultedmixture was used in a coating apparatus to coat the tablet cores.

Example 50

Dissolved 1.8 g methyl 4-hydroxybenzoate and 0.2 g propyl4-hydroxybenzoate in about 0.5 ml boiling water for injection. Aftercooling the solution to about 50° C., while stirring added 4 g lacticacid, 0.05 g propylene glycol and 4 g tipifarnib Form I or Form II orForm III or Form IV (active ingredient basis) of the present invention.The above solution was cooled to room temperature and q.s. with waterfor injection to 1 L. This resulted a solution containing 4 mg/mL oftipifarnib Form I or Form II or Form III or Form IV (active ingredientbasis). The solution was sterilized by filtration and filled in sterilecontainers.

Comparative Example 1

Slurry experiment in water: took 20 mg tipifarnib Form A of PreparationExample 1, 20 mg tipifarnib Form I, 20 mg Form II, 20 mg Form III and 20mg Form IV of the present invention, stirred in water respectively atroom temperature for 3 days, and then analyzed by XRD.

Starting form Test results Tipifarnib Form A Tipifarnib Form I TipifamibForm I Tipifamib Form I Tipifarnib Form II Tipifarnib Form II TipifarnibForm III Tipifarnib Form III Tipifarnib Form IV Tipifarnib Form IV

The results show that tipifarnib Form A transformed to tipifanib Form Iafter stirring in water at room temperature for 3 days, while tipifarnibForm I, Form II, Form III and Form IV of the present invention remainunchanged. It shows that tipifarnib Form I, Form II, Form III and FormIV of the present invention is more stable in water than the prior art.

All patents, patent application publications, patent applications andnon-patent publications cited in this specification are incorporatedinto this application by reference in their entireties.

The described above are only specific embodiments for illustrating thepresent invention, but without limiting it to that. Any changes oralternations, without creative work, made by those skilled in the artwithin the technical scope disclosed by the present invention, shouldfall within the scope of the present invention. Therefore, the scope ofprotection of the present invention shall be subject to the scope ofprotection defined in the claims.

What is claimed is:
 1. Tipifarnib Form I having the structure shown informula (I) below,

wherein, measured using Cu-Kα radiation, the X-ray powder diffractionpattern of the tipifarnib Form I, expressed as 2θ angles, has thefollowing characteristic peaks: 8.4°±0.2°, 11.9°±0.2°, 16.4°±0.2°,17.0°±0.2°, 18.5°±0.2° and 21.7°±0.2°.
 2. The tipifarnib Form Iaccording to claim 1, wherein the X-ray powder diffraction pattern ofthe tipifarnib Form I, expressed as 2θ angles, has the followingcharacteristic peaks: 8.4°±0.2°, 11.9°±0.2°, 15.3°±0.2°, 16.4°±0.2°,17.0°±0.2°, 18.0°±0.2°, 18.5°±0.2°, 20.4°±0.2°, 21.3°±0.2°, 21.7°±0.2°,24.8°±0.2° and 26.8°±0.2°.
 3. The tipifarnib Form I according to claim2, wherein the X-ray powder diffraction pattern of the tipifarnib FormI, expressed as 2θ angles, has the following characteristic peaks withtheir relative intensities: Diffraction angel 2θ Relative intensity % 8.4° ± 0.2° 60.2 11.9° ± 0.2° 34.6 12.7° ± 0.2° 16.7 14.0° ± 0.2° 9.315.3° ± 0.2° 28.4 16.4° ± 0.2° 82.7 17.0° ± 0.2° 72.3 17.4° ± 0.2° 32.218.0° ± 0.2° 33.8 18.5° ± 0.2° 100 19.9° ± 0.2° 13.2 20.4° ± 0.2° 55.220.8° ± 0.2° 28.2 21.3° ± 0.2° 61.5 21.7° ± 0.2° 61.9 22.9° ± 0.2° 34.124.1° ± 0.2° 16.1 24.8° ± 0.2° 48.8 25.5° ± 0.2° 11.1 26.8° ± 0.2° 62.527.3° ± 0.2° 16.7.


4. A method of preparing the tipifarnib Form I according to claims 1 to3, comprising any one of the following methods: 1) forming a suspensionof tipifarnib solids in a solvent, stirring for crystallization andprecipitation, and then separating crystals and drying to obtain thetipifarnib Form I; the solvent is selected from the group consisting ofethanol, n-propanol, water, nitromethane, acetone, ethyl acetate,isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, acetonitrile,dichloromethane, n-heptane, and any mixture thereof, preferably ethylacetate, acetonitrile, methyl tert-butyl ether, n-propanol, or anymixture thereof; preferably, the weight to volume ratio of tipifarnibsolids to the solvent is from 5 mg/1 mL to 100 mg/1 mL, more preferablyfrom 20 mg/1 mL to 50 mg/1 mL; preferably, the stirring time is from 4days to 5 days; preferably, the stirring is carried out at 10° C. to 40°C.; preferably, the drying temperature is from 10° C. to 40° C., thedrying time is from 10 hours to 48 hours; 2) forming a solution oftipifarnib solids in a solvent, then volatilizing to dryness to obtainthe tipifarnib Form I; the solvent is selected from the group consistingof ketones, esters, n-propanol, sec-butanol, n-butanol, water,tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, toluene andany mixture thereof, preferably acetone, dichloromethane, water,acetonitrile, or any mixture thereof; preferably, the weight to volumeratio of tipifarnib solids to the solvent is from 5 mg/1 mL to 50 mg/1mL, more preferably from 5 mg/1 mL to 25 mg/1 mL; preferably, the volumeratio of the two solvents in the solvent mixture is from 1:3 to 3:1;preferably, the volatilizing process is carried out at 25° C. to 40° C.;3) forming a solution of tipifarnib solids in a solvent, cooling forcrystallization and precipitation with stirring, and then separatingcrystals and drying to obtain the tipifarnib Form I; the solvent isselected from the group consisting of alcohols, ketones, esters,acetonitrile and any mixture thereof; preferably acetone or isopropanol;preferably, the weight to volume ratio of tipifarnib solids to thesolvent is from 40 mg/1 mL to 150 mg/1 mL, more preferably from 40 mg/1mL to 100 mg/1 mL; preferably, the temperature of forming solution isfrom 60° C. to 75° C., more preferably from 60° C. to 70° C.;preferably, the temperature of crystallization and precipitation is from−10° C. to 10° C., more preferably from −10° C. to 0° C.; preferably,the crystallization time is from 1 hour to 10 hours; 4) forming asolution of tipifarnib solids in a co-solvent, adding an anti-solvent,stirring for crystallization and precipitation, and then separatingcrystals and drying to obtain the tipifarnib Form I; the co-solvent isselected from the group consisting of alcohols, acetone, ethyl acetate,tetrahydrofuran, and nitromethane; preferably methanol, ethanol, acetoneor tetrahydrofuran; preferably, the weight to volume ratio of tipifarnibsolids to the co-solvent is from 10 mg/1 mL to 50 mg/1 mL, morepreferably from 10 mg/1 mL to 25 mg/1 mL; preferably, the anti-solventis selected from the group consisting of water, isopropyl ether, andn-heptane; preferably, the stirring time is from 3 minutes to 60minutes; preferably, the stirring is carried out at room temperature; 5)forming a suspension of amorphous tipifarnib in a solvent, stirring forcrystallization and precipitation, and then separating crystals anddrying to obtain the tipifarnib Form I; the solvent is selected from thegroup consisting of alcohols, ketones, esters, ethers, alkanes,tetrahydrofuran and acetonitrile; more preferably ethyl acetate oracetonitrile; preferably, the weight to volume ratio of amorphoustipifarnib to the solvent is from 20 mg/1 mL to 100 mg/1 mL, morepreferably from 20 mg/1 mL to 50 mg/1 mL; preferably, the stirring timeis from 10 minutes to 20 minutes, more preferably 10 minutes to 15minutes; preferably, the stirring is carried out at room temperature. 5.Tipifarnib Form II having the structure shown in formula (II) below,

wherein the tipifarnib Form II is monohydrate, and wherein, measuredusing Cu-Kα radiation, the X-ray powder diffraction pattern of Form II,expressed as 2θ angles, has the following characteristic peaks:5.3°±0.2°, 6.8°±0.2°, 8.5°±0.2°, 16.3°±0.2°, 18.0°±0.2° and 20.9°±0.2°.6. The tipifarnib Form II according to claim 5, wherein the X-ray powderdiffraction pattern of the tipifarnib Form II, expressed as 2θ angles,has the following characteristic peaks: 5.3°±0.2°, 6.8°±0.2°, 8.5°±0.2°,12.8°±0.2°, 13.8°±0.2°, 16.3°±0.2°, 16.9°±0.2°, 17.1°±0.2°, 18.0°±0.2°,18.5°±0.2°, 20.9°±0.2° and 27.9°±0.2°.
 7. The tipifarnib Form IIaccording to claim 6, wherein the X-ray powder diffraction pattern ofthe tipifarnib Form II, expressed as 2θ angles, has the followingcharacteristic peaks with their relative intensities: Diffraction angel2θ Relative intensity %  5.3° ± 0.2° 43.3  6.8° ± 0.2° 100  8.5° ± 0.2°44.4 12.8° ± 0.2° 16.2 13.8° ± 0.2° 12.9 16.3° ± 0.2° 45.7 16.9° ± 0.2°26.5 17.1° ± 0.2° 21.2 18.0° ± 0.2° 78.2 18.5° ± 0.2° 21.3 20.4° ± 0.2°8.4 20.9° ± 0.2° 28.1 21.5° ± 0.2° 6.9 21.9° ± 0.2° 9.9 22.3° ± 0.2° 6.623.6° ± 0.2° 11.6 24.1° ± 0.2° 9.8 27.1° ± 0.2° 11.3 27.9° ± 0.2° 15.728.9° ± 0.2° 12.4 30.8° ± 0.2° 10.4.


8. A method of preparing the tipifarnib Form II according to claims 5 to7, comprising any one of the following methods: 1) form a solution oftipifarnib solids in a solvent, then volatilizing to dryness to obtainthe tipifarnib Form II; the solvent is selected from the groupconsisting of methanol, ethanol, trifluoroethanol and any mixturethereof, preferably methanol; preferably, the weight to volume ratio oftipifarnib solids to the solvent is from 10 mg/1 mL to 50 mg/1 mL, morepreferably from 10 mg/1 mL to 30 mg/1 mL; preferably, the volatilizingprocess is carried out at 10° C. to 40° C., more preferably 10° C. to30° C.; 2) forming a suspension of amorphous tipifarnib solids in asolvent, stirring for crystallization and precipitation, and thenseparating and drying to obtain the tipifarnib Form II; the solvent isselected from the group consisting of an alcohol-water mixture, aketone-water mixture, a tetrahydrofuran-water mixture, a1,4-dioxane-water mixture, an acetonitrile-water mixture, and a dimethylsulfoxide-water mixture, preferably a dimethyl sulfoxide-water mixture;preferably, the volume percentage of water in the solvent is from 50% to100%, more preferably 85% to 100%; preferably, the weight to volumeratio of tipifarnib solids to the solvent is from 25 mg/1 mL to 100 mg/1mL, more preferably from 25 mg/1 mL to 35 mg/1 mL; preferably, thestirring time is from 10 minutes to 20 minutes, more preferably from 10minutes to 15 minutes; preferably, the stirring temperature is from 4°C. to 25° C.; preferably, the drying temperature is from 10° C. to 30°C., the drying time is from 10 hours to 24 hours; 3) placing amorphoustipifarnib solids in a humidity dessicator to obtain Form II; therelative humidity in the humidity dessicator is from 85% to 100%,preferably 97%; preferably, the placing time is from 1 day to 7 days,more preferably 1 day.
 9. Tipifarnib Form III having the structure shownin formula (III) below,

wherein Form III is sesquihydrate, and wherein, measured using Cu-Kαradiation, the X-ray powder diffraction pattern of the tipifarnib FormIII, expressed as 2θ angles, has the following characteristic peaks:6.2°±0.2°, 8.8°±0.2°, 15.9°±0.2° and 18.2°±0.2°.
 10. The tipifarnib FormIII according to claim 9, wherein the X-ray powder diffraction patternof the tipifarnib Form III, expressed as 2θ angles, has the followingcharacteristic peaks: 6.2°±0.2° 8.8°±0.2°, 13.2°±0.2°, 15.9°±0.2°,18.2°±0.2°, 19.8°±0.2°, 22.2°±0.2° and 26.1°±0.2°.
 11. The tipifarnibForm III according to claim 10, wherein the X-ray powder diffractionpattern of the tipifarnib Form III, expressed as 2θ angles, has thefollowing characteristic peaks with their relative intensities:Diffraction angel 2θ Relative intensity %  6.2° ± 0.2° 10.2  8.8° ± 0.2°100 12.4° ± 0.2° 4.1 13.2° ± 0.2° 7.3 15.9° ± 0.2° 23.9 18.2° ± 0.2°33.2 19.8° ± 0.2° 8.7 21.0° ± 0.2° 3.7 22.2° ± 0.2° 10.8 22.8° ± 0.2°4.4 24.1° ± 0.2° 6.9 26.1° ± 0.2° 9.9 27.6° ± 0.2° 6.6.


12. A method of preparing the tipifarnib Form III according to claims 9to 11, comprising any one of the following methods: 1) forming asolution of tipifarnib solids in a solvent, cooling with stirring forcrystallization and precipitation, and then separating crystals anddrying to obtain the tipifarnib Form III; the solvent is water andacetonitrile mixture or water and acetone mixture; preferably, thevolume percentage of water in the solvent is from 30% to 50%;preferably, the weight to volume ratio of tipifarnib solids to thesolvent is from 14 mg/1 mL to 25 mg/1 mL; preferably, the temperature offorming solution is from 60° C. to 70° C.; preferably, the temperatureof crystallization and precipitation is from −10° C. to 0° C.;preferably, the crystallization time is from 1 hour to 24 hours;preferably, the drying temperature is from 10° C. to 40° C., the dryingtime is from 10 hours to 24 hours; 2) forming a solution of tipifarnibsolids in a co-solvent, adding an anti-solvent, stirring forcrystallization and precipitation, and then separating crystals anddrying to obtain the tipifarnib Form III; the co-solvent is selectedfrom the group consisting of acetonitrile, 1,4-dioxane, butanone, andisopropyl acetate, preferably acetonitrile or 1,4-dioxane; preferably,the weight to volume ratio of tipifarnib solids to the co-solvent isfrom 2 mg/1 mL to 25 mg/1 mL, more preferably 10 mg/1 mL to 25 mg/1 mL;preferably, the anti-solvent is water or n-heptane; preferably, thestirring time is from 1 hour to 24 hours; preferably, the stirring iscarried out at room temperature; preferably, the drying temperature isfrom 10° C. to 40° C., the drying time is from 10 hours to 24 hours; 3)forming a solution of tipifarnib solids in a solvent, then volatilizingto dryness to obtain the tipifarnib Form III; the solvent is selectedfrom the group consisting of a nitromethane-water mixture, abutanone-water mixture, an acetonitrile-water mixture, atetrahydrofuran-water mixture, and a 1,4-dioxane-water mixture, morepreferably a butanone-water mixture or a nitromethane-water mixture;preferably, the weight to volume ratio of tipifarnib solids to thesolvent is from 5 mg/1 mL to 10 mg/1 mL; preferably, the volumepercentage of water in the solvent is from 1% to 10%; preferably, thevolatilizing temperature is from 10° C. to 30° C., more preferably from20° C. to 30° C.
 13. Tipifarnib Form IV having the structure shown informula (I) below,

wherein, measured using Cu-Kα radiation, the X-ray powder diffractionpattern of the tipifarnib Form IV, expressed as 2θ angles, has thefollowing characteristic peaks: 7.5°±0.2°, 13.9°±0.2°, 15.8°±0.2°,16.5°±0.2°, 17.4°±0.2° and 18.1°±0.2°.
 14. The tipifarnib Form IVaccording to claim 13, wherein the X-ray powder diffraction pattern ofthe tipifarnib Form IV, expressed as 2θ angles, has the followingcharacteristic peaks: 7.5°±0.2°, 13.9°±0.2°, 15.4°±0.2°, 15.8°±0.2°,16.5°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 20.7°±0.2°, 21.6°±0.2°, 24.3°±0.2°,26.5°±0.2° and 29.1°±0.2°.
 15. The tipifarnib Form IV according to claim14, wherein the X-ray powder diffraction pattern of the tipifarnib FormIV, expressed as 2θ angles, has the following characteristic peaks withtheir relative intensities: Diffraction angel 2θ Relative intensity % 7.5° ± 0.2° 51.8 13.9° ± 0.2° 22.1 15.4° ± 0.2° 20.4 15.8° ± 0.2° 42.316.5° ± 0.2° 100 17.4° ± 0.2° 24.7 18.1° ± 0.2° 23 18.9° ± 0.2° 13.420.7° ± 0.2° 18.4 21.6° ± 0.2° 11.1 23.0° ± 0.2° 16.7 24.3° ± 0.2° 1824.7° ± 0.2° 13 25.1° ± 0.2° 16.1 25.9° ± 0.2° 14.5 26.5° ± 0.2° 21.527.5° ± 0.2° 19.1 29.1° ± 0.2° 24.1.


16. A method of preparing the tipifarnib Form IV according to claims 12to 14, comprising: forming a solution of tipifarnib solids in a solvent,then evaporating to dryness to obtain the tipifarnib Form IV;preferably, the solvent is selected from ethanol and chloroform;preferably, the weight to volume ratio of tipifarnib solids to thesolvent is from 10 mg/1 mL to 25 mg/1 mL; preferably, the volatilizingprocess is carried out at 40° C. to 50° C.
 17. A pharmaceuticalcomposition comprising a therapeutically and/or preventively effectiveamount of an active pharmaceutical ingredient selected from the groupconsisting of the tipifarnib Form I according to any one of claims 1 to4, the tipifarnib Form II according to any one of claims 5 to 8, thetipifarnib Form III according to any one of claims 9 to 12, and thetipifarnib Form IV according to any one of claims 13 to 16, and at leastone pharmaceutically acceptable carrier.
 18. The pharmaceuticalcomposition according to claim 17, wherein the pharmaceuticalcomposition is selected from the group consisting of tablets, capsules,pills, powders, asolutions, syrups, suspensions, elixirs and injections.19. Use of the tipifarnib Form I according to any one of claims 1 to 4,the tipifarnib Form II according to any one of claims 5 to 8, thetipifarnib Form III according to any one of claims 9 to 12 or thetipifarnib Form IV according to any one of claims 13 to 16 for thepreparation of a medicament for treating and/or preventing of abnormalcell growth diseases; the diseases include but not limited to solidtumors and blood cancers associated with RAS mutation or overexpression, such as lung cancer, pancreatic cancer, colon cancer,thyroid follicular cancer, myelodysplastic syndrome, interstitial celltumor, melanoma, teratoma, neuroblastoma, glioma, epidermal carcer suchas head and neck squamous cell carcinoma, salivary gland cancer, skinbenign tumor, breast cancer, kidney cancer, bone cancer, ovarian cancer,bladder cancer, liver cancer, multiple neurofibromatosis, hematologiclymphoma such as peripheral T lymphoma, myeloid leukemia,myelodysplastic syndrome (MDS), chronic granulocytic leukemia, and soon.
 20. A method of treating and/or preventing of abnormal cell growthdiseases, the method comprising administering to a patient in needthereof a therapeutically and/or prophylactically effective amount ofone or more of the tipifarnib Form I according to any one of claims 1 to4, the tipifarnib Form II according to any one of claims 5 to 8, thetipifarnib Form III according to any one of claims 9 to 12, thetipifarnib Form IV according to any one of claims 13 to 16 or thepharmaceutical composition according to any one of claims 17 to 19; theabnormal cell growth diseases include, but are not limited to, solidtumors and blood cancers associated with RAS mutation or overexpression, such as lung cancer, pancreatic cancer, colon cancer,thyroid follicular cancer, myelodysplastic syndrome, interstitial celltumor, melanoma, teratoma, neuroblastoma, glioma, epidermal cancer suchas head and neck squamous cell carcinoma, salivary gland cancer, skinbenign tumor, breast cancer, kidney cancer, bone cancer, ovarian cancer,bladder cancer, liver cancer, multiple neurofibromatosis, hematologiclymphoma such as peripheral T lymphoma, myeloid leukemia,myelodysplastic syndrome (MDS), chronic granulocytic leukemia, and soon.